A single dose of ketamine enhances early life stress-induced aggression with no effect on fear memory, anxiety-like behavior, or depression-like behavior in mice

Ketamine, a dissociative anesthetic with antidepressant effects in humans, can worsen aggression in mice exposed to early life stress. In a mouse model, chronic social isolation followed by acute foot shock produced lasting excessive aggression. A single 10 mg/kg dose of ketamine given before the foot shock selectively increased aggression measured seven days later, without affecting sociability, anxiety, depression-like behavior, or locomotion. The findings suggest ketamine may specifically target aggression-related brain circuitry distinct from circuits governing other moods. Caution is advised when using ketamine for disorders linked to early life stress.

Study at a glance

Abstract

Ketamine is a dissociative anesthetic that has been shown to have antidepressant effects in humans and has been proposed as a potential treatment for mood disorders such as PTSD and aggression. However, previous studies from our lab and others have demonstrated that ketamine’s effects are highly context- and dose-dependent. In a recent study, we found that 10 mg/kg ketamine could exacerbate the effects of early life stress on excessive aggression in mice. To further investigate the effect of ketamine on moods, such as fear, anxiety, depression, and aggression, we used a mouse model of early life stress, involving chronic social isolation followed by acute traumatic stress in the form of non-contingent, unpredictable foot shock during adolescence. We find this is necessary to induce long-lasting excessive aggression in a novel environment. 7–8-week-old socially isolated mice were given IP injections of 10 mg/kg ketamine 30 minutes before being subjected to foot shock and then assessed 7 days later for changes in sociability, aggression, mobility, anxiety-like behavior, and depression-like behavior. The results show that ketamine selectively increases long-lasting aggression in mice exposed to foot shock, but does not affect mood-related behaviors or locomotion. These findings suggest that during early life stress, ketamine may exert its effects by specifically targeting aggression brain circuitry that is distinct from brain circuits responsible for non-aggressive social or emotional behaviors. Therefore, while ketamine may be a promising treatment for various mood disorders, caution should be exercised when using ketamine to treat disorders associated with early life stress.